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The synthesis of active pharmaceutical ingredients (APIs)using continuous flow chemistryMarcus Baumann* and Ian R. Baxendale*
Review Open Access
Address:Department of Chemistry, Durham University, South Road, DH1 3LEDurham, United Kingdom
Email:Marcus Baumann* - [email protected];Ian R. Baxendale* - [email protected]
* Corresponding author
Keywords:continuous processing; flow synthesis; in-line analysis; manufacture;pharmaceuticals; scalability
Beilstein J. Org. Chem. 2015, 11, 1194–1219.doi:10.3762/bjoc.11.134
Received: 01 May 2015Accepted: 06 July 2015Published: 17 July 2015
Associate Editor: J. A. Murphy
© 2015 Baumann and Baxendale; licensee Beilstein-Institut.License and terms: see end of document.
AbstractThe implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry
and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially
relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic
systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demon-
strating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation
and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses
using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader
will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall
process.
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IntroductionThe last 20 years have witnessed a true renaissance in the way
synthetic chemistry is performed due to the implementation of
various enabling technologies allowing the modern synthesis
chemist to select from a range of tools and equipment to best
perform a given transformation [1-6]. The trend to question the
suitability of classical laboratory glassware and to utilise more
‘fit for purpose’ synthesis equipment not only allows the indi-
vidual chemists to conduct their research in a more modern
fashion, but also adjusts their mind-set towards the full prac-
tical breadth of synthesis planning. In this way chemists are
more aware of the entire processing sequence, considering
quenching, work-up, extraction and purification as part of the
holistic design of the preparative route. The introduction of such
thinking earlier in a compound’s development pipeline signifi-
cantly simplifies the scaling transitions required to meet the
increasing quantities of material needed for the different stages
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Figure 1: Pharmaceutical structures targeted in early flow syntheses.
of biological and regulatory testing and then on into the
building of the manufacturing route.
Arguably one of the most widely amenable of the enabling tech-
nologies is flow chemistry, which accommodates small foot-
print reactors in which streams of substrates and reagents can be
united to react in a highly controlled and reproducible environ-
ment [7-15]. Importantly, regulation of many parameters such
as heat and mass transfer, mixing and residence times are much
improved over related batch processes. Advantageously the
flow reactor configuration can also be readily customised to
meet the specific demands of the reaction and the continuous
processing requirements. The construction of the reactor is
often modular being assembled from several specialised yet
easily integrated components such as heating and cooling zones,
micro-mixers, residence tubing coils, separators, and diagnostic/
analysis units. This workflow not only allows for facile automa-
tion and continuous operation of such processes, but also
enables the chemist to perform more potentially hazardous and
otherwise forbidden transformations in a safer and more reli-
able fashion [16-21]. The main advantages cited for improved
operational safety are principally the reduced inventories of
reactive chemicals, the small contained reactor units and the
ability to install real time monitoring of the system leading to
rapid identification of problems and the instigation of auto-
mated safe shutdown protocols. Furthermore, the use of direct
in-line purification and analysis techniques can be implemented
thus generating a more streamlined and information enriched
reaction sequence [22-26]. Consequently, numerous studies
have been published in recent years detailing the beneficial
outcome of flow chemistry applied to single or indeed multi-
step syntheses of target compounds on various reaction scales
[27-34]. At the same time a number of limitations and chal-
lenges to the wider adoption of flow chemistry have been iden-
tified including reactor fouling, high investment costs and
training of the next generation of chemists needed in order to
embrace the value of these modern synthesis instruments [35-
39].
In order to evaluate the current standing of this field, we will
review and discuss several flow based API’s syntheses
conducted by scientists from both academia and industry. It is
hoped that the reader will through this review gain a greater
appreciation of the range of flow chemistries that have already
been successfully performed as well as knowledge of some of
the more common pitfalls and limitations. Recognition of the
problematic aspects of flow chemistry is essential to allow a
unified effort from the chemistry and chemical engineering
communities in order to surmount these obstacles and for us to
achieve the vision of true continuous manufacture of pharma-
ceuticals.
ReviewEarly flow processing approachesThe first published examples of flow chemistry applied to the
synthesis of pharmaceutically active molecules emerged in the
early 2000s when several research groups reported on specific
flow transformations that enabled a new synthesis of these
known pharmaceuticals. Examples of these early endeavours
include the syntheses of efaproxiral (1) and rimonabant (2)
using a AlMe3-mediated direct amidation in flow [40], an im-
proved metalation step in the scaled synthesis of NBI-75043 (3)
[41], a continuous dehydration process to deliver over 5 kg of
dehydropristane 4, a precursor of the immunoactivating agent
pristane [42] or the flow synthesis of hydroxamic acids by a
procedure that was also applied to the preparation of suberoyl-
anilide hydroxamic acid (5, SAHA, Figure 1) [43]. Another
early application of microreactor technology was reported in
2005 detailing the assembly and subsequent decoration of the
fluoroquinolinone scaffold 6 resulting in the synthesis of a
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Scheme 1: Flow synthesis of 6-hydroxybuspirone (9). Inserted photograph reprinted with permission from [45]. Copyright 2008 American ChemicalSociety.
library of analogues including the well-known antibiotic
ciprofloxacin (6, R1 = cyclopropyl, R2 = piperazinyl) [44].
An important early industry-based example was disclosed by
scientists at Bristol-Myers Squibb in 2008 detailing a flow ap-
proach towards converting the psychotropic agent buspirone (7)
into its major active metabolite, 6-hydroxybuspirone (9) [45].
This work comprised three consecutive flow steps including a
low-temperature enolisation of buspirone (7). The subsequent
reaction of the enolate with gaseous oxygen in a trickle-bed
reactor was coupled to a direct in-line quench of the reaction
mixture to yield 6-hydroxybuspirone (Scheme 1).
This approach furthermore made use of in-line analysis tech-
niques like FTIR (for the monitoring of the enolisation step) and
was successfully run at steady state for 40 h generating the
target compound at multi-kilogram scale. As this paper states,
the main advantages of a continuous approach over batch
processing in this scale-up campaign were found to be related to
safety, isolated purity and economics.
The successful outcome of the above study can in part be
ascribed to the use of a static mixing device which allowed for
the selective and clean mono-deprotonation under scale-up
conditions. This was in stark contrast to the related batch
scenarios which were difficult to control. Owing to the impor-
tance of efficient micro-mixing attainable in continuous
processing another interesting reactor design coined as a
‘continuous oscillatory baffled reactor’ (COBR) was intro-
duced. In this set-up the reactor stream being processed is
directed into a tubular reactor which contains periodically
spaced annular baffles thereby creating a series of eddies
through oscillatory motion simultaneously applied to the reactor
(Figure 2) [46]. The resulting vigorous axial and radial mixing
results in very sharp residence time distributions and excellent
heat and mass transfer. Consequently, long batch processes
(including crystallisations, fermentations, polymerisations or
waste water treatments) can be translated into a continuous
process. In an early example such COBRs were applied to the
flow synthesis of aspirin showcasing the effectiveness of this
reactor type during a week long campaign delivering the target
compound at scale with very high product purity (99.94%) and
minimal loss of product during cleaning (<0.005%) [47].
In 2009 a flow synthesis of a high volume pharmaceutical was
reported by the McQuade group describing a three step ap-
proach towards ibuprofen (16) using microreactor technology
[48]. A fully continuous process was aspired to, in which only
final purification was to be performed off-line at the end of the
sequence. Each of the individual steps were first optimised in
flow being mindful of the reagents used in order to avoid down-
stream incompatibilities. The initial step was a Friedel–Crafts
acylation of isobutylbenzene (10) with propionic acid (11) in
the presence of excess triflic acid (12). The transformation was
found to work very effectively and the acid catalyst was also
tolerated in the subsequent 1,2-aryl migration step. This was
mediated by a hypervalent iodine reagent, PhI(OAc)2 (13),
conducted in trimethyl orthoformate (14, TMOF) and methanol
(Scheme 2). The direct saponification of the resulting
rearranged methyl ester with an excess of base thus completed
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Figure 2: Configuration of a baffled reactor tube (left) and its schematic working principle (right).
Scheme 2: McQuade’s flow synthesis of ibuprofen (16).
the telescoped flow synthesis of ibuprofen (16). Work-up, via
acidification and repeated washes with ether, water and brine,
followed by filtration, evaporation, treatment with active carbon
and finally recrystallisation was performed manually to eventu-
ally yield pure ibuprofen product (99%). Overall this pioneering
work allowed for the synthesis of ibuprofen in only ten minutes
residence time albeit in a yield of only 51% equating to a
productivity of 9 mg/min.
Although this work nicely demonstrates the feasibility of
constructing a continuous process it is mainly an academic
proof of principle based upon an important well known mole-
cule. We state this not to detract from the work but to comment
here about the different approaches and considerations that gen-
erally focus the minds of academics and industrialists and use
this example as illustration.
This route would certainly not constitute an economically viable
approach compared to the existing manufacturing routes which
have been highly refined and optimised [49-51]. Although
modern reagents such as hypervalent iodine and triflic acid
represent very valuable additions to the chemists’ repertoire
they are also inherently expensive and difficult to source at
scale. In addition the waste streams generated through their use
would also be difficult and costly to dispose. This aptly leads to
an interesting relationship that is often encountered in innova-
tive work employing new technologies where a general mind
set exists to also test the limits of modern reagent equivalents in
addition to the equipment. From an academic perspective this is
a positive and beneficial contribution to the progression of the
subject, however, this can significantly restrict the translational
value of the methodology with respect to adoption or conveni-
ent uptake by industry. Commonly industry cites cost, unaccept-
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Scheme 3: Jamison’s flow synthesis of ibuprofen sodium salt (17).
able solvent combinations and limited availability of new
reagents (metal ligand combinations) at scale as the main
hindrances to uptake. This message is certainly being acknowl-
edged with many of the more recent publications originating
from academia using industry evaluation metrics and reagent
selection guides to influence their route selection.
However, it is not only academia which is in the firing line,
industry scientists are often heavily criticised as being too
reliant on existing reactions/reagents and therefore being too
conservative and resistant to change. Although this is often a
corporate promoted strategy resulting from being risk adverse it
can bias mind sets to fall back on the proven rather than inno-
vate and explore. The additional pressures of meeting regula-
tory compliance, which is often easier based upon precedent,
and the constant ‘time = money’ equation also compound the
effect. Again such perceptions are changing with many compa-
nies creating specialist innovation groups dedicated to explo-
ration and exploitation of new technologies. Fledgling innova-
tions are in-house tested, monitored and if viable rolled out
more expansively throughout the company. An excellent illus-
tration would be the adoption of microwave reactors which
have become primary heating methods in many medicinal
chemistry labs. This is also being seen in the adoption of flow
processing technologies where all the major pharmaceutical
companies have internal teams working on business critical
projects as well as longer term objectives. Furthermore the
generation of various consortia between academia and industry
is also influencing the transfer of knowledge, reasoning and
importantly expectations. All these considerations are helping to
drive the area of flow chemistry.
Flow processing scenariosRecently, the Jamison laboratory reported on an improved flow
synthesis of the ibuprofen sodium salt (17) that delivers the
target compound in only three minutes residence time with an
improved productivity of about 135 mg/min [52]. As the key
steps are the same as in McQuade’s approach (Friedel–Crafts
acylation, 1,2-aryl migration and saponification) this report
focuses on improved output by intensifying the overall
sequence (Scheme 3). As such an in-line extraction is per-
formed after the Friedel–Crafts acylation step, followed by
dissolving intermediate 18 in trimethyl orthoformate and DMF.
This stream is then combined with a stream of ICl (21) to affect
the 1,2-aryl migration in a heated flow reactor (1 min, 90 °C)
followed by treatment of the stream with NaOH, 2-mercap-
toethanol, MeOH and water in order to hydrolyse the intermedi-
ate methyl ester and quench residual ICl. After collection of the
crude reaction mixture an extractive work-up was performed
off-line, in which ibuprofen was generated upon acidification
from its sodium salt 17.
Another high profile pharmaceutical for which a flow synthesis
has been developed is imatinib (23), the API of Novartis’ tyro-
sine kinase inhibitor Gleevec [53-55]. Reported by the Innova-
tive Technology Centre (ITC) in 2010, this landmark synthesis
was realised as a continuous process featuring an amide forma-
tion, a nucleophilic substitution and a Buchwald–Hartwig
coupling as key synthesis steps performed in flow (Scheme 4).
Further highlights of this approach were the use of scavenger
resins for intermediate purification and solvent switching opera-
tions as well as the use of in-line UV-monitoring needed to
orchestrate the various reagent streams. Although the low solu-
bility of various intermediates proved challenging, the designed
route was able to successfully deliver sufficient quantities of
imatinib (23) and several of its analogues (~30–50 mg each) in
high purity within one working day allowing subsequent testing
of new derivatives. Although this approach was conducted as a
fully integrated telescoped continuous flow sequence its
capacity to run as an uninterrupted process is certainly limited
by the solid-phase scavengers employed as purification aids.
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Scheme 4: Flow synthesis of imatinib (23).
Scheme 5: Flow synthesis of the potent 5HT1B antagonist 28.
The stoichiometric scavenging capacity of many of these
species coupled with their limited loadings does restrict the
quantities of material which can be generated in a run. As a
consequence this approach is better suited to the rapid forma-
tion of small quantities of directly purified material for
screening purposes but does not constitute a viable mode of
performing direct large scale manufacture.
In the same year the ITC also reported on their efforts towards
the flow syntheses of two lead compounds reported earlier by
AstraZeneca. The first one details the flow synthesis of a potent
5HT1B antagonist (28) that was assembled through a five step
continuous synthesis including a SNAr reaction, heterogeneous
hydrogenation, Michael addition–cyclisation and final amide
formation (Scheme 5) [56]. This sequence again makes use of
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Scheme 6: Flow synthesis of a selective δ-opioid receptor agonist 33.
in-line scavenging resins for purification purposes and demon-
strates the utility of in-line solvent switching protocols and high
temperature reactor coils operating at 130–245 °C, well above
the boiling points of the solvents employed.
In the second study, the flow synthesis of the selective δ-opioid
receptor agonist 33 was discussed (Scheme 6) [57]. Again, a
strategy of integrating each of the three synthetic steps with a
sequenced cascade of scavenger agents to perform the aspects
of work-up and purification was used.
The report also showcased the generation and use of organo-
metallic species (i.e., Grignard reagents) in flow synthesis as
well as in-line React-IR monitoring in order to precisely control
the onset of late stage flow streams that are affected by disper-
sion effects thus marking the first use of this now commonly
incorporated analysis technique.
As the safe use of organometallic reagents has emerged as a key
facet of flow chemical synthesis [58], the ITC reported on the
design and implementation of a dual injection loop system that
could deliver solutions of organometallic reagents (i.e.,
LiHMDS or n-BuLi) as a pseudo-continuous process [59]. This
protocol enables loading of a second loop with the unstable
organometallic reagent whilst the first loop (previously filled
with the same solution) is being directed to the intended flow
transformation. Once this first reagent loop is empty, an auto-
mated protocol switches the valves so that the second loop
transfers the reagent, whilst the first one is being recharged.
This concept was successfully applied to the flow synthesis of a
20-member library of casein kinase I inhibitors (38) that also
demonstrate the selective mono-bromination, heterocycle
formations and high temperature SNAr reactions as key flow
steps in the sequence (Scheme 7).
One of the early published examples of industry-based research
on multi-step flow synthesis of a pharmaceutical was reported
in 2011 by scientists from Eli Lilly/UK and detailed the syn-
thesis of fluoxetine 46, the API of Prozac [60]. In this account
each step was performed and optimised individually in flow,
with analysis and purification being accomplished off-line. The
synthesis commences with the reduction of the advanced inter-
mediate ketone 47 using a solution of pre-chilled borane–THF
complex (48) to yield alcohol 49 (Scheme 8). Conversion of the
pendant chloride into iodide 51 was attempted via Finckelstein
conditions, however, even when utilising phase-transfer condi-
tions in order to maintain a homogeneous flow regime the
outcome was not satisfactory giving only low conversions.
Alternatively direct amination of chloride 49 utilising high
temperature flow conditions (140 °C) allowed the direct prepar-
ation of amine 50 in excellent yield. Flow processing using a
short residence time (10 min) at the elevated temperature
allowed for a good throughput; in addition, the handling of the
volatile methylamine within the confines of the flow reactor
simplifies the practical aspects of the transformation, however,
extra precautions were required in order to address and remove
any leftover methylamine that would pose a significant hazard
during scaling up.
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Scheme 7: Flow synthesis of a casein kinase I inhibitor library (38).
Scheme 8: Flow synthesis of fluoxetine (46).
The final arylation of 50 was intended to be performed as a
SNAr reaction, however, insufficient deprotonation of the
alcohol 50 under flow conditions (NaHMDS or BEMP instead
of using a suspension of NaH as used in batch) required a modi-
fication to the planned approach. To this end a Mitsunobu
protocol based on the orchestrated mixing of four reagent
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Scheme 9: Flow synthesis of artemisinin (55).
streams (50, 54 and reagents 52 and 53) was developed and
successfully applied to deliver fluoxetine (46) in high yield.
Overall, this study is a good example detailing the intricacies
faced when translating an initial batch synthesis into a sequence
of flow steps for which several adaptations regarding choice of
reagents and reaction conditions are mandatory in order to
succeed.
The flow synthesis of the high profile antimalaria agent
artemisinin (55) was reported by the Seeberger group in 2012
[61,62]. This intriguing approach represents one of the few
examples where photochemistry has been employed in the syn-
thesis of a pharmaceutical. For this endeavour dihydroar-
timisinic acid (56), an advanced building block that is available
via chemoselective batch reduction of bioengineered artemisinic
acid (57), was chosen as the starting point. The key transforma-
tions to yield artemisinin thus demanded a reaction cascade
including a singlet oxygen mediated ene-reaction, a Hock
cleavage of the resulting hydroperoxide 58 followed by oxi-
dation with triplet oxygen and a final peracetalisation
(Scheme 9).
Based on previous work by the Seeberger group and others [63-
65] a simple flow photoreactor set-up comprising of a layer of
FEP-polymer tubing wrapped around a cooled medium pres-
sure mercury lamp was used to efficiently generate and react the
singlet oxygen in the presence of tetraphenylporphyrin (TPP) as
a photosensitizer. Upon exiting the photoreactor, the reaction
stream was acidified by combining with a stream of TFA in
order to enable the remaining reaction cascade to take place in a
subsequent thermal reactor unit. After off-line purification by
silica gel chromatography and crystallisation artemisinin was
isolated in 39% yield equating to an extrapolated productivity
of approximately 200 g per day.
More recently, Seeberger and McQuade reported on further
improvements of this strategy enabled by the development of a
NaBH4-based flow reduction procedure of artemisinin (55) to
yield dihydroartemisinin (61) as well as in-line purifications and
derivatisations to also generate several related malaria medica-
tions (i.e., β-artemether (62), β-artemotil (63) and α-artesunate
(64)) in an efficiently telescoped manner (Scheme 10) [66,67].
As the authors mention, their work is related to an earlier study
by researchers from the Universities of Warwick and Bath
describing a continuous reduction protocol of artemisinin using
LiBHEt3 in 2-Me-THF as a greener solvent [68]. Although this
reductant is more expensive than NaBH4 this approach
convinces through its simplicity and superior productivity
(~1.6 kgh−1L−1).
Beside the use of photochemical processing towards the syn-
thesis of artemisinin and its derivatives, this strategy has also
been employed in the flow synthesis of a carprofen analogue
[69] as well as in the regioselective bromination towards a rosu-
vastatin precursor [70] showcasing how continuous flow photo-
chemistry is receiving a significant level of interest. This is not
least because of the perceived green reagent concept of photons
and the ability to overcome the inherent dilution problems en-
countered in batch. The ability to control residence times and
hence decrease secondary transformations whilst using the
small dimensions of the microreactor flow streams to enhance
the photon flux has been claimed to increase productivity.
However, it should be noted that many of the articles promoting
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Scheme 10: Telescoped flow synthesis of artemisinin (55) and derivatives (62–64).
the use of flow photochemistry do not currently adequately
quantify or describe the systems in sufficient detail in order to
fully justify such statements [65]. This is a general considera-
tion but especially pertinent to the use of low power LED’s
which are becoming increasingly popular. The calibration and
quantification of the incident light from such devices is not
normally evaluated or even commented upon in many of these
studies hence reproducibility is therefore a major issue. Consid-
ering one of the main drivers of flow chemistry is an increase in
reproducibility this seems a rather negative trend.
In 2012 researchers from AstraZeneca (Sweden) reported upon
a scale-up campaign for their gastroesophageal reflux inhibitor
programme. Specifically, flow chemical synthesis was used to
efficiently and reliably provide sufficient quantities of the target
compound AZD6906 (65), which had been prepared previously
in batch. From these earlier batch studies concerns had been
raised regarding exothermic reaction profiles as well as product
instability which needed to be addressed when moving to larger
scale synthesis. Flow was identified as a potential way of
circumventing these specific problems and so was extensively
investigated. The developed flow route [71] started with the
reaction of methyl dichlorophosphine (66) and triethyl ortho-
acetate (67), which in batch could only be performed under
careful addition of the reagent and external cooling using dry
ice/acetone. Pleasingly, a simple flow setup in which the two
streams of neat reagents were mixed in a PTFE T-piece main-
tained at 25 °C was found effective in order to prepare the
desired adduct 68 in high yield and quality showcasing the
benefits of superior heat dissipation whilst also safely handling
the toxic and pyrophoric methyl dichlorophosphine reagent
(Scheme 11).
As the subsequent Claisen condensation step was also known to
generate a considerable exotherm, a similar flow setup was used
in order to allow the reaction heat to dissipate. The superiority
of the heat transfer process even allowed this step to be per-
formed on kilogram quantities of both starting materials (68,
69) at a reactor temperature of 35 °C giving the desired product
72 within a residence time of only 90 seconds. Vital to the
successful outcome was the efficient in situ generation of LDA
from n-BuLi and diisopropylamine as well as the rapid
quenching of the reaction mixture prior to collection of the
crude product. Furthermore, flow processing allowed for the
reaction of both substrates in a 1:1 ratio (rather than 2:1 as was
required in batch) as the immediate quenching step prevented
side reactions taking place under the strongly basic conditions.
Having succeeded in safely preparing compound 72 on kilo-
gram scale, the target compound 65 was then generated by
global deprotection and subsequent recrystallisation where
batch was reverted to as the conditions had been previously
devised and worked well.
As seen above, avoiding detrimental exotherms in scale up
campaigns is a common reason for developing a continuous
flow process. This approach is also demonstrated in the syn-
thesis of the pyrrolotriazinone 73 via a exothermic oxidative
rearrangement from 75, a key intermediate towards brivanib
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Scheme 11: Flow approach towards AZD6906 (65).
Scheme 12: Pilot scale flow synthesis of key intermediate 73.
Scheme 13: Semi-flow synthesis of vildagliptine (77).
alaninate (74) that was reported by researchers at BMS in 2014
(Scheme 12) [72].
Another application that undoubtedly benefits from performing
scale up processes continuously concerns the generation and use
of the Vilsmeier reagent (76). An early study by scientists at
Roche (UK) demonstrated an approach in which Auto-MATE
equipment combined with reaction simulation software was
used to predict heat flow data for making and using Vilsmeier
reagent at scale [73]. Using this information the formylation of
3,5-dimethoxyphenol was then performed at multi-kilo scale
showing good agreement of the results with the devised simula-
tions. More recently, scientists at Novartis (Switzerland)
extended this study by developing a semi-continuous flow ap-
proach for the synthesis of the oral antidiabetic vildagliptine
(77) using in situ generated Vilsmeier reagent (Scheme 13)
[74].
Neat streams of DMF and POCl3 were mixed in a simple Teflon
T-piece before entering a tubular reactor maintained at 22 °C
(4.5 mL, tres = 30 s). Upon exiting this reactor the crude stream
of the Vilsmeier reagent 76 was combined with a stream of
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Scheme 14: Pilot scale asymmetric flow hydrogenation towards 83. Inserted photograph reprinted with permission from [75]. Copyright 2012 Amer-ican Chemical Society.
amide 80 in DMF that was prepared in situ in a batch reactor
from proline amide and chloroacetyl chloride. The crude nitrile
product 81 was then collected in a batch vessel and isolated in
pure form after crystallisation and washing with n-heptane.
Alkylation of 81 with the corresponding amino-adamantane
derivate in the presence of excess K2CO3 following an existing
batch protocol completed the synthesis of vildagliptine (77).
Again, it was highlighted that the control of the exothermic
Vilsmeier reagent formation and subsequent handling of this
toxic and unstable intermediate was ideally suited to a contin-
uous production and consumption in flow protocol.
Gaseous reagents in flowAnother example in which flow chemical synthesis was used
as the key step in an industrial setting was reported by scien-
tists from Eli Lilly (USA) in 2012. An asymmetric high-
pressure hydrogenation towards LY500307 (82) [75] was
demonstrated (Scheme 14). As this campaign aimed to
produce the key intermediate 83 at pilot-scale, a flow-based
asymmetric hydrogenation was chosen as an economically more
viable option compared to establishing a high-pressure batch
process.
As depicted in Scheme 14, solutions of the substrate 84 and a
zinc triflate additive were combined with the rhodium precata-
lyst (85, 0.025 mol %, and Josiphos ligand 86) before being
mixed with hydrogen gas and entering a plug flow tubular
reactor (volume 1.46 or 73 L, hydrogen pressure 70 bar, 70 °C,
residence time 12 h). Several campaigns were run over periods
of several days (e.g., campaign 1: 282 hours total cumulative
reagent feed time) in order to evaluate this hydrogenation
process. The process proved robust allowing reproducible and
safe generation of the desired product in both high yield
and enantiomeric excess. Additionally, semi-continuous
liquid–liquid extraction, in-line distillation and product crys-
tallisation were coupled to this hydrogenation step allowing for
a total of 144 kg of the product 83 to be produced, purified and
isolated using equipment that fits into existing laboratory fume
hoods and hydrogenation bunkers. As the authors point out, this
flow process not only delivered the hydrogenation product 83
with an improved safety profile at pilot-scale in a cost-effective
manner, but moreover gave the same weekly throughput as a
400 L plant module operating in batch mode.
As the preceding examples clearly illustrate flow chemistry has
quickly proven a viable means to assemble complex target
molecules in a continuous and more modern fashion thus
starting to satisfy claims regarding its advantageous nature
compared to batch synthesis. Whilst some of these early exam-
ples can be seen as proof of concept studies, others have already
demonstrated the application of further strategic elements
including in-line purification and in-line analysis, both being
crucial in order the achieve multistep flow synthesis. As the
reader will see in the following part of this review, further
advancements are geared towards more readily scaled processes
and will also include the development of new devices allowing
safe and efficient use of gaseous reagents as well as more effec-
tive ways of quickly transitioning between very low and very
high temperatures that are key for streamlining modern flow
synthesis routes.
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Scheme 15: Flow synthesis of fanetizole (87) via tube-in-tube system.
Although the widely used H-Cube system had provided a
popular solution for safe and convenient hydrogenation reac-
tions at lab scale [76-79], the safe utilisation of other gaseous
reagents at above ambient pressure was a relatively neglected
area in flow chemistry for a long time. Only a few examples of
flow hydrogenations and carbonylations had been reported [80-
83]. The redevelopment and commercialisation of a laboratory
based tube-in-tube reactor by the Ley group in 2009 changed
the playing field and popularised the wider use of gases and
volatile components. The design of the tube-in-tube system is
based on a semipermeable Teflon AF2400 tubing (1 mm o.d.,
0.8 mm i.d.) being housed within a wider PTFE tube (3.2 mm
o.d., 1.6 mm i.d.; Figure 3). Depending on the intended applica-
tion the gas can be fed either into the inner or the outer tube and
upon pressurisation penetrates into the reagent stream where the
desired reaction occurs. It has also been shown that an applied
vacuum can enable the extraction of gaseous substances from a
flow stream.
Figure 3: Schematic representation of the ‘tube-in-tube’ reactor.
This concept has since been studied in a variety of applications
using for instance O3, CO, H2, CO2, O2, NH3 or syngas and has
been reviewed very recently [84]. One noteworthy application
of the tube-in-tube system by the Ley group in 2013 details the
flow synthesis of the anti-inflammatory agent fanetizole (87)
[85], in which ammonia gas was fed into the inner tube, whilst
the outer tube contains a solution of phenethylisothiocyanate
(89) in DME. The tube-in-tube system was placed onto the
cooling unit of a Polar Bear Plus system maintained at 0 °C in
order to generate the urea adduct 90 in quantitative yield
(Scheme 15). In order to prepare the target compound this flow
stream was then combined with an additional stream of
bromoacetophenone (91) and passed through a heated tubular
reactor unit (100 °C, 15 min) furnishing the 2-aminothiazole
core of fanetizole (87). Due to preceding studies on the use of
ammonia gas in this tube-in-tube system including in-line titra-
tions only a minimal excess of gas (1.06 equivalents) was
necessary to obtain complete conversion in the initial reaction
subsequently allowing safe scale-up with a productivity of 70 g
fanetizole (87) in 7 h.
In 2013 the Jamison group reported the flow synthesis of the
important H1-antagonist diphenhydramine·HCl (92) show-
casing the potential of modern flow chemistry to adhere to
green chemistry principles (minimal use of organic solvents,
atom economy etc.) [86]. The synthetic strategy relied on
reacting chlorodiphenylmethane (93) with an excess of
dimethylaminoethanol (94) via a nucleophilic substitution reac-
tion (Scheme 16).
As both starting materials are liquid at ambient temperature the
use of a solvent could be avoided allowing direct generation of
the hydrochloride salt of 92 in a high temperature reactor
(175 °C) with a residence time of 16 min. Conveniently at the
same reaction temperature the product was produced as a
molten paste (m.p. 168 °C) which enabled the continued
processing of the crude product circumventing any clogging of
the reactor by premature crystallisation. Analysis of the crude
extrude product revealed the presence of minor impurities
(<10%) even when stoichiometric amounts of 94 were used,
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Scheme 16: Flow synthesis of diphenhydramine.HCl (92).
Scheme 17: Flow synthesis of rufinamide (95).
consequently an in-line extraction process was developed. Ad-
ditional streams of aqueous sodium hydroxide (3 M, preheated)
and hexane were combined with the crude reaction product fol-
lowed by passage through a membrane separator. The hexane
layer was subsequently collected and treated with hydrochloric
acid (5 M in IPA) leading to the precipitation of diphen-
hydramine hydrochloride (92) in high yield (~90%) and purity
(~95%). Furthermore, options to further reduce waste gener-
ated during the purification sequence are presented by
combining hot IPA with the crude flow stream leading to the
isolation of the target compound (92·HCl) by direct crystallisa-
tion in the collection vessel (yield 71–84%, purity ~93%,
productivity 2.42 g/h).
More recently, the Jamison group also reported upon a short
flow synthesis of the antiepileptic agent rufinamide (95) [87].
The 1,2,3-triazole ring was prepared via a dipolar cycloaddition
between an in situ generated benzylic azide and propiolamide
(also prepared in situ), which by maintaining a low inventory of
the reactive intermediate reduced the safety concerns asso-
ciated with the use of the azide. The choice of flow when
handling hazardous materials like azides is a very frequently en-
countered driver and several publications detailing the asso-
ciated benefits have emerged over the years [88-90]. Impor-
tantly in this study, a flow reactor consisting of copper tubing
maintained at 110 °C (6.2 minutes residence time) was
employed as this would release small amounts of copper salts
catalysing the regioselective triazole formation. A cautionary
note regarding the potential of generating copper azide within
the reactor should be made here from a scale-up perspective as
this was not explored in the paper. Overall, this small scale
syringe pump based set-up enabled the preparation of rufin-
amide (95) within ~11 minutes processing time and with a
productivity of ~0.22 g/h, although this does not take into
account the time required for work-up and purification neces-
sary to isolate the pure rufinamide (Scheme 17).
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Scheme 18: Large scale flow synthesis of rufinamide precursor 102.
Although the above approach generates rufinamide (95) in a
continuous fashion, a more convincing strategy towards rufin-
amide has been reported by the Hessel laboratory in 2013 [91].
Their route focused upon a dipolar cycloaddition between azide
100 and (E)-methyl 3-methoxyacrylate (101) to yield triazole
102 that was converted into rufinamide (95) (Scheme 18).
The benefits of using this alternative dipolarophile 100 are that
it is not only considerably cheaper and less toxic than 98, but it
also delivers the desired 1,4-triazole regioisomer without the
need for a metal catalyst that requires stringent purification
afterwards. Due to the reduced reactivity of 100 the crucial
cycloaddition step was conducted neat at elevated temperature
(210 °C) yielding pure 102 within short residence times
(5–30 minutes studied) on 20–200 mmol scale after crystallisa-
tion (70–83% yield).
As in the case of rufinamide (95), the choice of the flow reactor
also plays a key role in the synthesis of meclinertant (SR48692,
103), which is a potent probe for investigating neurotensin
receptor-1 [92]. The flow synthesis of this challenging com-
pound was reported in 2013 and aims to evaluate the benefits of
flow chemistry in order to avoid shortcomings of previous batch
synthesis efforts particularly in regard to scale up [93]. The
investigation first involved the preparation of the key aceto-
phenone starting material 112 which although commercially
available was expensive and could be generated from 1,3-cyclo-
hexadione (104). The sequence consisted of O-acetylation, a
Steglich rearrangement, oxidation and a final methylation reac-
tion. As the use of flow chemistry had already improved the
O-acetylation during scale-up tests (130 mmol) by avoiding
exotherms, it was anticipated that the subsequent Steglich
rearrangement could be accomplished in flow using catalytic
DMAP instead of stoichiometric AlCl3 as precedented
(Scheme 19). This was eventually realised by preparing a
monolithic flow reactor functionalised with DMAP that proved
far superior to commercially available DMAP on resin.
Employing the monolithic reactor cleanly catalysed the
rearrangement step when a solution of 106 was passed through
the reactor at elevated temperature (100 °C, 20 min residence
time). The resulting triketone 107 was telescoped into an iodine
mediated aromatisation, followed by high temperature mono-
methylation using dimethyl carbonate/dimethylimidazole as a
more benign alternative to methyl iodide at scale.
The subsequent Claisen condensation step between ketone 112
and diethyl oxalate (113) was reportedly hampered by product
precipitation and clogging problems, thus a pressure chamber
was developed [94] that would act as a pressure regulator
allowing this step to be scaled up in flow in order to provide
114 on multigram scale (134 g/h). A Knorr pyrazole formation
between 114 and commercially available hydrazine 115 had
previously been found difficult to scale up in batch (the yield
dropped from 87% to 70%) and was thus translated into a high
temperature flow protocol (140 °C) delivering the desired prod-
uct 116 in 89% yield (Scheme 20). Ester hydrolysis and a
triphosgene (118) mediated amide bond formation between acid
117 and adamantane-derived aminoester 119 [95] completed
this flow synthesis. Meclinertant (103) was subsequently
obtained after batch deprotection using polymer supported
sulfonic acid. Overall, this study showcases how flow chem-
istry can be applied to gain benefits when faced with problems
during mesoscale synthesis of a complex molecule. However,
despite the successful completion of this campaign, it could be
argued that the development time required for such a complex
molecule in flow can be protracted; therefore both synthetic
route and available enabling technologies should be carefully
examined before embarking upon such an endeavour.
New flow heating approachesOne of the main advantages of flow chemistry is the safety and
ease with which reactions can be performed continuously at
elevated temperatures. With the exception of flow microwave
constructs [96-101] all other reactor types rely on convective
heat transfer. Although this is rapid for small reactor dimen-
sions as the scale of the device increases the efficacy of the
heating rapidly falls. The Kirschning group has introduced
inductive heating (IH) as an energy stimulus for continuous
flow synthesis [102,103]. In this scenario magnetic or conduc-
tive materials (metal beads, nanoparticles, etc.) are placed
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Scheme 19: First stage in the flow synthesis of meclinertant (103).
Scheme 20: Completion of the flow synthesis of meclinertant (103).
Beilstein J. Org. Chem. 2015, 11, 1194–1219.
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Scheme 21: Flow synthesis of olanzapine (121) utilising inductive heating techniques.
within a reactor cartridge exposed to an oscillating magnetic
field of medium (15–25 kHz) or high frequency (780–850 kHz)
leading to very rapid heating of reagent streams pumped
through the reactor. A powerful application of this new concept
was demonstrated in the flow synthesis of the atypical neurolep-
ticum olanzapine (121) [104]. The synthesis begins with a
Buchwald–Hartwig coupling between 2-iodonitrobenzene (122)
and 2-aminothiophene 123 enabled by inductive heating
(Scheme 21).
After in-line extraction and filtration through a silica packed
cartridge, the resulting reaction stream was mixed with triethyl-
silane (124) and telescoped into a Pd-doped fixed bed reactor in
order to affect smooth reduction of the nitro group. The output
stream was then collected, and reintroduced to a flow reactor to
be combined with a stream of dilute hydrochloric acid and
passed through an inductively heated tubular reactor main-
tained at 140 °C to furnish benzodiazepine 125 in 88% yield
after 30 h processing time. The flow synthesis of olanzapine
(121) was completed by directing a mixture of benzodiazepine
125 and N-methylpiperazine (126) through a final inductively
heated reactor containing Ti-doped Magsilica (85 °C, 83% after
15 h processing). Whilst this study did not aim to produce olan-
zapine at scale it aptly demonstrates the successful develop-
ment and adaptation of inductive heating to the flow synthesis
of this important pharmaceutical.
The Kirschning group (2013) also demonstrated a multi-step
flow synthesis of the antidepressant amitriptyline (127) [105].
They developed a sequence harnessing reactions at several
different temperature regimes allowing processing of low
temperature lithiation and carboxylation reactions, ambient
temperature Grignard addition and the high temperature elimi-
nation of water.
In the process solutions of 2-bromobenzylbromide (128) and
n-BuLi are delivered into a small tubular flow reactor main-
tained at −50 °C in order to perform a Wurtz-type coupling. The
resultant aryllithium intermediate passes into a tube-in-tube
reactor, where carboxylation takes place furnishing the lithium
carboxylate 129. Excess carbon dioxide is subsequently
removed using a degassing tube before reacting species 129
with a further stream of n-BuLi to induce cyclisation to
dibenzosuberone (130) in a short total residence time of
33 seconds (Scheme 22). Finally, the stream of 130 was
combined with 3-(dimethylamino)propylmagnesium chloride
(131) to affect a Grignard addition at ambient temperature fol-
lowed by passage through an inductively heated reactor
(210 °C, 810 kHz, 36 seconds residence time) which under the
acidic conditions promotes dehydration. The product is isolated
as the in situ formed hydrochloride salt of amitriptyline (127).
Solution deliveryAs the previous examples have demonstrated, the development
of an efficient flow process is often the result of designing and
implementing a new concept or piece of equipment that is better
suited to performing an otherwise challenging task. One aspect
of continuous flow synthesis for which little progress was made
for a long time concerned the way in which reagents streams
were delivered into the reactors. In much of the early flow
chemistry work delivery of liquid streams was achieved using
simple syringe pumps. Unfortunately syringe pump applica-
Beilstein J. Org. Chem. 2015, 11, 1194–1219.
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Scheme 22: Flow synthesis of amitriptyline·HCl (127).
tions are significantly limited by relatively low working pres-
sures and often needed manual intervention when recharging
the syringe which precluded a fully continuous and automated
process. Alternatively the use of piston or rotary pumps (i.e.,
HPLC pumps) could be employed but these also have draw-
backs being often characterised by inaccurate flow rates or
fouling over prolonged periods of use due to their direct interac-
tions with the chemicals being pumped (for continuous flow
applications not using a sample loop). In addition both of these
pumping solutions require homogeneous solutions where partic-
ulates or precipitates (slurries) are extremely detrimental. These
shortcomings obviously impact the performance of flow reac-
tors when attempting reaction scale-up, especially when precise
and consistent reagent delivery is crucial.
In order to address these issues flow equipment utilising
adapted peristaltic pumps have been developed and applied to
several mesoscale syntheses utilising common organometallic
reagents (i.e., n-BuLi, Grignard reagents, DIBAL-H) [106]. The
pump design uses specific fluorinated polymers for the feed
tubing that is placed on the rotor of a modified peristaltic pump
resulting in a smooth and consistent delivery of a solution that
can be drawn directly out of the supplier’s reagent bottle. A first
application of a commercial system was reported by the Ley
group with their continuous synthesis of the important anti-
cancer agent tamoxifen (132) in 2013 [106]. The synthesis starts
with a halogen–lithium exchange reaction between arylbromide
133 and n-BuLi at −50 °C and the subsequent addition of the
formed aryllithium species to ketone 134 at the same tempera-
ture (Scheme 23). After exiting the cold reactor zone, this
stream passes through a coil maintained at 30 °C in order to
ensure the complete consumption of the ketone 134.
The resulting solution of lithium alkoxide 135 is combined with
a further stream containing trifluoroacetic anhydride (TFAA)
before being mixed with a stream of triethylamine in order to
promote the elimination of the activated tertiary alcohol. A
good isolated yield of (E/Z)-tamoxifen (132) (84%, E/Z ratio
25:75) was achieved after trituration with hot hexanes. As this
report states, the peristaltic pumping module used in this syn-
thesis permitted a production of almost 13 g of (E/Z)-tamoxifen
over a period of only 80 minutes, providing sufficient material
for one patient’s treatment for 900 days.
As this example demonstrates, flow chemistry can be used as a
means to facilitate the direct synthesis of a supply of pharma-
ceuticals from a small dedicated reactor. This enables the quick
and easy relocation of manufacturing to permit medications to
be made bespoke at the site of requirement or in future applica-
tions on demand as required by the patient or prescriber.
It is also worth highlighting here two European initiatives in
this regrad, namely CoPIRIDE [107] and the F³ Factory which
have both focused on developing new technologies, processes
and manufacturing concepts towards the “chemical plant of the
future” [108]. One of the specific goals of the CoPIRIDE
project was the design of a small footprint modular chemical
plant to be embedded in a standard EU 20-foot ISO norm
container (3 × 12 m storage container). Extensive use of flow
chemistry and microreactor technologies were used to create a
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Scheme 23: Flow synthesis of E/Z-tamoxifen (132) using peristaltic pumping modules.
'plug-and-play', container-based production facility (Figure 4).
The challenge was to create a flexible facility that could be
easily reconfigured to generate multiple chemical outputs as
required. This shift towards greater versatility and a smaller
environmental footprint also provide for the easy and rapid
redeployment of the unit at a new geographical location making
it more capable of adapting to market trends and changing
manufacturing demands. Several working units have been
assembled and successfully used for a range of chemistries
including hydroformulations, biodiesel and acrylic acid produc-
tion and large scale polymerisation reactions [109].
Flow manufacturingWhereas the previous applications have demonstrated how flow
chemistry can enable the rapid preparation of several pharma-
ceuticals by focusing on the synthetic effort, the final examples
in this review showcase how flow synthesis can be linked to
in-line assaying of new molecules as well as the continuous
manufacture and formulation of drug compounds.
In 2013 the Ley group disclosed a study detailing the flow syn-
thesis of a library of GABAA agonists which was linked to
in-line frontal affinity chromatography (FAC) in order to
directly generate binding affinity data for these new entities
towards human serum albumin (HSA), a highly abundant
protein in human blood plasma [110].
Figure 4: Container sized portable mini factory (photograph credit:INVITE GmbH, Leverkusen Germany).
The synthesis of a small collection of imidazo[1,2-a]pyridine
derivatives was realised through the application of different
scavenger resins for in-line purification as well as a number of
liquid handlers to orchestrate the library synthesis effort
(Scheme 24). Using this semi-automated process a small collec-
tion of 22 imidazo[1,2-a]pyridines 136 was prepared within
four working days. The synthetic route consisted of an aldol
condensation between various acetophenones 137 and ethyl
glyoxylate (138). This was followed by an HBF4-catalysed
cyclocondensation of the resulting Michael acceptor 139 with
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Scheme 24: Flow synthesis of imidazo[1,2-a]pyridines 136 linked to frontal affinity chromatography (FAC).
various 2-aminopyridines 140 and subsequent derivatisation of
the ester group into the corresponding acid or amide moiety.
In order to directly perform the FAC analysis on these struc-
tures an HPLC column (15 µL volume) was filled with
commercially available HSA protein and connected to a HPLC
system. After establishing the void volume of this column, two
different literature known marker compounds (diclofenac
sodium and isoniazid) were used in order to calibrate the system
based on their retention time which could be directly correlated
to the protein binding affinity. Furthermore, as the compound
library contained zolpidem (142) and alpidem (143) (Figure 5),
two FDA approved drugs for which affinity data were already
literature reported the authors were able to validate their method
by matching their affinity data.
Figure 5: Structures of zolpidem (142) and alpidem (143).
Using this setup, solutions of the remaining imidazo[1,4-
a]pyridines (600 µL, 67.5 µM) were passed through the binding
assay column allowing quick determinations of their HSA
binding affinity. This proof of concept study therefore marks
one of the first published reports where flow chemical syn-
thesis is combined with direct biological evaluation of new
structures thus linking chemistry with biology using standard
flow equipment.
A second application demonstrating the power of this paradigm
shift towards improving the hit-to-lead and lead optimisation
was published in 2013 by researchers at Cyclofluidics, a
company dedicated to the acceleration of preclinical discovery
processes [111]. In this work a platform capable of designing a
virtual chemical space was presented that further integrates the
synthesis, purification and screening of the newly designed
entities. Analogue optimisation was accomplished by running
several microfluidic synthesis-screening loops that establish key
SAR data. This approach was exemplified by synthesising a
small library of Abl kinase inhibitors with the synthesis aspect
focusing on the Sonogashira coupling between heterocyclic
alkynes (hinge binder motif) and a selection of aryl iodides
and bromides (DFG-binder motif) based on the common benz-
amide scaffold of ponatinib (144, R = N-methyl piperazine,
Het = imidazopyridazine) and related pyrazole-ureas (145)
(Scheme 25).
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Scheme 25: Synthesis and screening loops in the discovery of new Abl kinase inhibitors.
Figure 6: Schotten–Baumann approach towards LY573636.Na (147).
As depicted schematically in Scheme 25 the development cycle
commences with the microfluidic synthesis of a new analogue
followed by its in-line analysis (LC–MS) and purification (by
passage through a silica cartridge). The clean compound is then
assayed allowing the resulting activity profile to be fed into a
design algorithm which determines which compound to next
prepare and test. Using this repeating loop approach led the
cyclofluidics scientists to the discovery of the pyrazole-urea
motif 145 as a potential replacement of the more common benz-
amide systems 144.
In 2014 researchers from Eli Lilly (US) disclosed a detailed
study regarding the synthesis of LY2886721 (146), a then
promising inhibitor of beta-amyloid cleaving enzyme (BACE).
Their work focussed on evaluating flow techniques for the key
amide bond forming step under modified Schotten–Baumann
conditions [112]. This work was related to earlier studies
at Eli Lilly detailing a continuous synthesis of the anticancer
agent LY573636 .Na (147 , Figure 6) that also used a
Schotten–Baumann reaction as key step [113]. The driving
force in the development of a continuous process was in both
cases to minimise exposure of individuals to hazardous ma-
terials by means of fewer unit operations, and more importantly
the development of the concept of ‘tech transfer by truck’
meaning that once established, a continuous process could be
easily replicated at a different location without need for major
investments.
As the effort to prepare LY2886721 targeted a pilot-scale
process (up to 10 kg/72 h) high concentrations of diamine 150
and acid chloride 151 had to be successfully handled. The
amide formation was conducted in a plug flow reactor followed
directly by reactive crystallisation in a mixed suspension, mixed
product removal (MSMPR) crystalliser (Scheme 26).
Because of the high concentrations and potential for solid for-
mation peristaltic pumps were used to direct solutions of di-
amine 150 (in EtOH/water/THF 2:2:1) and acid chloride 151
(prepared in situ with oxalyl chloride in MeCN/cat. DMF) via a
static mixer into a plug flow reactor (60 °C, up to 60 seconds
residence time). The desired amide product 146 (as its
hydrochloride) was rapidly formed in both high yield (>99%)
and purity (>98%). Importantly, maintaining a temperature of
60 °C ensured that reactor fouling by precipitation did not occur
despite the supersaturation of the product stream. The feed
stream of 146 (hydrochloride) was passed into a surge tank
(70 °C) and was subsequently directed into mixing elbows
where it was combined with a stream of aqueous NaOH leading
to the formation of the free-based 146 that would subsequently
crystallise in the crystalliser (30 min residence time). This also
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Scheme 26: Pilot scale flow synthesis of LY2886721 (146).
required adhering to high specifications regarding crystal size
and morphology. The sequence could be performed at scale and
in an improved throughput of 139 g/h (vs 33 g/h as achieved in
batch) yielding 9.44 kg of 146 over 72 h (yield of 94.1%).
Overall, the success of this flow campaign was attributed to
the improved reactive crystallisation as well as the relatively
low process and equipment costs compared to earlier batch
efforts.
A final application was recently reported by a research team at
MIT detailing a continuous flow process towards aliskiren
hemifumarate (152), including synthesis, purification, formula-
tion and tableting, thus demonstrating the continuous manufac-
ture of a pharmaceutical [114]. This achievement was enabled
by constructing a compact plant module (2.4 m × 7.3 m2) that
can produce aliskiren (152) at a rate of 45 g/h equating to
2.7 million tablets per year. The synthetic sequence starts with
the lactone ring opening of the very advanced intermediate 153
using amine 154 (10 equiv) and additive 155 (1 equiv) in a
tubular reactor (100 °C, 4 h residence time) to furnish amide
156. Importantly, as 156 was at this stage melted, no reaction
solvent was required for this step (Scheme 27).
The exiting, hot melt stream was mixed combined with EtOAc
and water to solubilise and extract the desired product into the
organic layer. The organic phase was directed into a mixed
suspension, mixed product removal (MSMPR) crystalliser
where upon cooling and addition of heptane as an anti-solvent a
slurry formed. After additional processing (washing/filtration)
the amide slurry of 156 was telescoped into a further sequence
furnishing aliskiren fumarate. This involved Boc deprotection,
quenching, in-line extraction and final salt formation. The
continuous formulation process also requires addition of an
excipient (SiO2) prior to drying, which results in the generation
of a solid cake that after grinding provides a tractable powder of
152 on SiO2. This material is mixed with 6000 Da PEG (35:65
mass ratio) and continuously fed into a heated extruder unit in
order to mix and melt the components prior to tableting. Impor-
tantly, the tablets prepared successfully passed various quality
control tests (visual appearance, size and dosage) and as
residual impurities and solvents were found within specifica-
tions could be released as final formulated drugs.
Overall this application of continuous drug manufacture high-
lights the standing within the field by showcasing how a final
dosage form of a pharmaceutical can be produced in a highly
automated and continuous fashion by linking chemical syn-
thesis and purification to direct formulation and final tableting.
It still however remains to be demonstrated that a more compre-
hensive and fully integrated continuous synthesis and tableting
sequence can be achieved. Although this work is an impressive
achievement it should be acknowledged that the preparation
involves only very limited and trivial chemistry. However, we
have in the preceding parts of this review highlighted many
impressive achievements demonstrating complex synthesis so
all the individual components required to perform the unifica-
tion have now been conducted. It will therefore only be a short
time until more elaborate and convincing examples of end-to-
end manufacturing are reported.
ConclusionAs this review has clearly demonstrated, flow chemistry has
matured from an innovative synthesis concept for improving
chemical synthesis to a powerful and widely applicable tool box
enabling the efficient multistep synthesis of numerous active
pharmaceutical ingredients. Whilst the original developments
came mainly from academic proof of concept studies the rapid
uptake and disclosure of flow syntheses has now generated
Beilstein J. Org. Chem. 2015, 11, 1194–1219.
1216
Scheme 27: Continuous flow manufacture of alikiren hemifumarate 152.
sufficient knowledge and equipment to execute any conceiv-
able flow synthesis. Furthermore, this has inspired considerable
progress in the linking of continuous synthesis to in-line purifi-
cation, biological assaying, and indeed formulation of medica-
tions. At this point it remains to be seen as to whether contin-
uous synthesis and manufacture of pharmaceuticals will be
applied primarily to small volume drugs and personalised medi-
cines, or if its benefits regarding safety, scale-up and automa-
tion will render continuous processing a key element across
more higher volume products. Current estimates suggest a
general increase in industrial applications of continuous manu-
facture of pharmaceuticals from 5% to 30% over the next few
years. Various pharma corporations as well as regulatory
authorities (FDA etc.) have fully advocated the use of contin-
uous manufacture. Nevertheless, a number of bottlenecks still
remain to be addressed in order to allow the community to fully
appreciate and exploit the true value of continuous synthesis
and manufacture. For one, it seems that there is still a signifi-
cant gap between many flow approaches developed by acad-
emic groups and those needed to solve problems in industrial
campaigns, however, exchange of experience by specific case
studies is starting to bridge these discrepancies. Furthermore,
with the commercialisation (and eventually reduced cost) of
various modular flow reactors one can expect a further increase
in flow-based applications. This trend might also be backed by
the changing mind-set of the practitioner becoming more accus-
tomed and confident in building and operating different flow
reactors rather than relying on traditional batch based lab equip-
ment. Crucial to this trend will be the training of students in
flow chemistry by academics, which currently is clearly lagging
behind expectation and demand. For this reason universities
should be encouraged to develop lecture courses and practical
classes to provide training in flow based chemical synthesis at
undergraduate and postgraduate student level. If these adjust-
ments can be made within the next few years, we can expect a
continuing advancement of the field and the continuous manu-
facture of pharmaceuticals should become a common practice
rather than a novel exception.
AcknowledgementsSupport from the Royal Society (to MB and IRB) is gratefully
acknowledged.
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1217
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